Introduction: Checkpoint Inhibition in NSCLC

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Moderator Corey J. Langer, MD, introduces a panel discussion focused on frontline treatment approaches and evolving maintenance strategies for patients with advanced non-small cell lung cancer (NSCLC), including discussion on immunotherapy, second-generation TKIs, and molecular medicine. The conversation includes in-depth perspective from Mark G. Kris, MD, Benjamin P. Levy, MD, Mark A. Socinski, MD, and Heather A. Wakelee, MD.

Early results for antibodies against PD-1 and PD-L1 have sparked enthusiasms amongst lung cancer experts, remarks Levy. Historically, immunotherapeutic approaches have not been effective in lung cancer; however, these new agents seem to be ushering in a new era.

Results for the anti-PD-1 inhibitor nivolumab in heavily pretreated patients with NSCLC were presented at the World Conference on Lung Cancer in October, explains Levy. This trial enrolled 129 patients with NSCLC and demonstrated an overall response rate (ORR) of 17% with an approximate 18-month median duration of response. Moreover, Levy notes, the median overall survival (OS) for all doses and histologies was 9.5 months. However, at the 3 mg/kg dose that will be explored in phase III trials, the median OS increased to 14.9 months, Levy points out.

In general, the toxicity profile for nivolumab was manageable, with less than 5% of patients experiencing grade 3/4 adverse events, Levy suggests. These agents do still have toxicity, Levy warns, but overall they are very well tolerated.

In addition to nivolumab, the PD-1 immune checkpoint inhibitor MK-3475 also demonstrated activity in highly pretreated patients with NSCLC, Langer notes. In this investigation, the ORR was 21% with an initial immune-related response of 24%. The duration of response with MK-3475 was durable and the median PFS is around 2 months, Langer states.

In addition to antibodies against PD-1, the compound MPDL3280A directly targets the ligand PD-L1, Wakelee states. This treatment currently has less data than the PD-1 inhibitors but seems to have similar efficacy and safety. Interestingly, Wakelee suggests, the checkpoint inhibitors demonstrated high responses in patients with a smoking history, suggesting these tumors may be immunogenic.

PD-L1 expression is being explored as a possible biomarker of response for both PD-1 and PD-L1 inhibitors. At this point, separate assays are being utilized along with each agent, making cross comparison between studies difficult. However, in a subset of 6 patients with high PD-L1 expression, the response rates were over 80% for patients treated with PD-1 inhibitors, Wakelee notes. Although, the panelists agree that patients still seem to respond, regardless of PD-L1 expression. In some situations, only patients expressing PD-L1 are being enrolled into clinical trials.

Response to these agents is dependent on both PD-L1 expression and the number of T-cells, remarks Kris. In many way, these agents work very similarly to targeted therapies. However, it may be difficult to get an accurate biopsy from a small metastatic lesion, specifically when considering heterogeneity, Kris notes. This draws into question the accuracy of selecting patients based on PD-L1 findings from metastatic lesions. As a result, Levy believes it is too early to exclude patients from treatment with PD-1 and PD-L1 inhibitors based only on PD-L1 expression by IHC.

These agents are clearly more effective in PD-L1-positive patients, Socinski notes. In terms of bringing a highly effective new drug to the market, selecting based on PD-L1 may initially be an effective strategy. Once approved, research can then focus on larger populations, Socinski believes.